Protomatter was among the most highly valued commodities in a region of the Delta Quadrant, reputed to be "the best source of energy in the quadrant". Neelix had dealt with protomatter when he worked as a trader, which in one instance led to conflict with the Kazon. He owned a containment cylinder designed to hold a small quantity of protomatter.

"Proto-matter" was referenced in the first draft script of VOY: "Death Wish", to have been established during the Big Bang. However, this was ultimately replaced with a reference to baryonic particles instead.

In the novel Foul Deeds Will Rise, Captain James T. Kirk and the crew of the Enterprise-A participate in crucial disarmament talks for two planets, with some of the natives attempting to finish the war by stealing one of the protomatter warheads that are being destroyed as part of the peace process and launching the warhead at a major city on the other planet, but these efforts are thwarted thanks to the actions of Spock, Montgomery Scott, and the redeemed Lenore Karidian.

In the The Genesis Wave trilogy, Captain Jean-Luc Picard reads a summary of the Genesis project that includes the observation that the instability of the Genesis planet was caused due to it being created from the remains of the Mutara Nebula rather than the protomatter being the problem in itself, speculating that the Genesis effect would have been successful if it had been used on a lifeless planet as it had been originally intended.

In the Star Trek Online mission "Echoes of Light", while aiding a recently warp-capable species, the Lukari, was their first major test flight through space, they discover a planet wiped clean by protomatter. The Lukari captain, Kuumaarke, mentions that protomatter can actually be quite stable if you know how to work with it right. In their investigation, the player character learns that the Tzenkethi had set off a protomatter bomb, wiping out all life on the planet. It is later discovered that the Tzenkethi have developed additional protomatter weapons and were detonating them on other inhabited worlds in distant parts of the Alpha quadrant.